Subclinical hypothyroidism is a biochemical diagnosis characterized by elevated thyrotropin (TSH) levels with normal circulating thyroxine (T4) and triiodothyronine (T3) levels. Although SCH does not present with symptoms of clinical hypothyroidism it may be associated with mood, cognitive, and physical symptoms, and increased risk for hyperlipidemia and ischemic heart disease. SCH may also increase vulnerability to depression, cognitive impairment, and dementia. SCH is relatively common and occurs in approximately five to ten percent of the population, with higher prevalence (up to 20%) in women over age 60. To date, there have been no well designed, controlled studies that have evaluated the neuropsychiatric effects of SCH on the most vulnerable population (i.e., elderly individuals), and the impact of thyroid hormone treatment in this group, despite the well documented association between thyroid dysfunction and mood and cognitive disturbance. The purpose of this proposal is to evaluate depression and neuropsychological function in non-demented, elderly individuals with SCH and the efficacy of T4 treatment in improving mood and cognition in these subjects. There are two phases to the proposed study. In phase I, we will employ a cross- sectional design to evaluate the specific nature, severity and pattern of mood, cognitive, and physical symptoms in elderly, non-demented participants with SCH compared with euthyroid controls. In the second phase, we will carry out a double-blind, placebo- controlled, sixteen week study of the effect of T4 in improving these measures in the SCH subjects. Mood, cognition, quality of life, physical symptoms of hypothyroidism and thyroid status (T4, T3, TSH and antithyroperoxidase (anti-TPO) antibodies) will be measured. This study will yield important information about the neuropsychiatric effects of SCH on a vulnerable population and the effect of thyroid hormone treatment in reducing symptoms and improving overall functioning. Public Health Relevance: This project aims to determine whether there are specific alterations of mood and cognition with mild thyroid failure, also known as subclinical hypothyroidism. Furthermore, this research will also address whether alterations of mood and cognition associated with subclinical hypothyroidism are improved with thyroid hormone treatment. [unreadable] [unreadable] [unreadable]